chrX-32573618-A-G

Variant names:

• chrX-32573618-A-G
• rs370644567
• NM_004006.3:c.1724T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP3 PP5 BS2_Supporting

The NM_004006.3(DMD):​c.1724T>C​(p.Leu575Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,209,011 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000062 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.000013 (0 hom. 3 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:10
• Conservation: PhyloP100: 7.71
• Publications: 2 publications found

Genes affected

DMD (HGNC:2928): (dystrophin) This gene spans a genomic range of greater than 2 Mb and encodes a large protein containing an N-terminal actin-binding domain and multiple spectrin repeats. The encoded protein forms a component of the dystrophin-glycoprotein complex (DGC), which bridges the inner cytoskeleton and the extracellular matrix. Deletions, duplications, and point mutations at this gene locus may cause Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), or cardiomyopathy. Alternative promoter usage and alternative splicing result in numerous distinct transcript variants and protein isoforms for this gene. [provided by RefSeq, Dec 2016]

DMD Gene-Disease associations (from GenCC):

• Becker muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• dilated cardiomyopathy 3B

  Inheritance: XL Classification: DEFINITIVE Submitted by: Ambry Genetics
• Duchenne and Becker muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• Duchenne muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• progressive muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836
• PP5: Variant X-32573618-A-G is Pathogenic according to our data. Variant chrX-32573618-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161220.
• BS2: High AC in GnomAd4 at 7 XL,AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.1724T>C	p.Leu575Pro	missense_variant	Exon 15 of 79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.1724T>C	p.Leu575Pro	missense_variant	Exon 15 of 79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes AF: 0.0000623 AC: 7 AN: 112270 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000950

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000128 AC: 14 AN: 1096741 Hom.: 0 Cov.: 30 AF XY: 0.00000828 AC XY: 3 AN XY: 362159

African (AFR) AF: 0.0000379 AC: 1 AN: 26379

American (AMR) AF: 0.00 AC: 0 AN: 35184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19375

East Asian (EAS) AF: 0.00 AC: 0 AN: 30185

South Asian (SAS) AF: 0.00 AC: 0 AN: 54120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.0000155 AC: 13 AN: 840794

Other (OTH) AF: 0.00 AC: 0 AN: 46051

GnomAD4 genome AF: 0.0000623 AC: 7 AN: 112270 Hom.: 0 Cov.: 23 AF XY: 0.0000872 AC XY: 3 AN XY: 34422

African (AFR) AF: 0.00 AC: 0 AN: 30903

American (AMR) AF: 0.0000950 AC: 1 AN: 10531

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3607

South Asian (SAS) AF: 0.00 AC: 0 AN: 2713

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.000113 AC: 6 AN: 53292

Other (OTH) AF: 0.00 AC: 0 AN: 1502

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:2

Dec 31, 2018

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The best available variant frequency is uninformative because there are too few occurrences in population data. Statistically enriched in uncharacterized patients compared to unmatched population data. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in a known repetitive region of the protein. Statistically associated with disease in multiple families. (p < 0.05) -

Dec 26, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 11, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variant in a gene in which most reported pathogenic variants are truncating/loss-of-function; This variant is associated with the following publications: (PMID: 25637381, 21104870, 33644936, 36409343) -

not specified Uncertain:3

Sep 04, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DMD c.1724T>C; p.Leu575Pro variant (rs370644567), is reported in the literature in multiple individuals affected with dystrophinopathies (Veerapandiyan 2010). This variant is reported as uncertain significance/likely pathogenic/pathogenic in ClinVar (Variation ID: 161220), and is only observed on two alleles in the Genome Aggregation Database. The leucine at codon 575 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Leu575Pro variant is uncertain at this time. References: Veerapandiyan A et al. Pseudometabolic presentation of dystrophinopathy due to a missense mutation. Muscle Nerve. 2010 Dec;42(6):975-9. -

May 04, 2022

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 22, 2015

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Given the suspicious case data and absence in unselected individuals we consider this variant a variant of uncertain significance, probably disease causing. The variant has been seen in at least 3-4 presumably unrelated individuals with elevated CKs and, in some cases, other signs of muscle disease. Veerapandiyan et al (2010) reported three unrelated boys with exertional myalgia, muscle stiffness, myoglobinuria and normal nuerological exam who all carried this variant. Two of the three boys had dystophin imunostaining and Western blot analysis of skeletal muscle, which was normal. All three had elevated CKs. Their phenotypes are summarized here: They specifically note that two of the boys had echos and ECGs, which were normal. The authors also report that the subjects had extensive work-ups for other causes of their phenotypes and that the variant is in the rod domain. They note that other rod domain variants have been associated with mild phenotypes like this. To the author’s knowledge these three individuals have not developed cardiomyopathy. They do get screening echos. The variant was reported online in the Leiden muscular dystrophy database in two individuals. No clinical data is provided for one. The other is noted to have recurrent rhabdomyolysis. In silico analysis with PolyPhen-2 predicts the variant to be damaging (0.998). The leucine at codon 575 is highly conserved across species. The variant was reported online in 1 of 43,652 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of September 16, 2015). Specifically, the variant was observed in 1 of 23,874 European individuals. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -

Becker muscular dystrophy Pathogenic:1 Uncertain:1

Mar 12, 2019

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Dec 21, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Duchenne muscular dystrophy Pathogenic:1 Uncertain:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic, low penetrance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 575 of the DMD protein (p.Leu575Pro). This variant is present in population databases (rs370644567, gnomAD 0.002%). This missense variant is significantly enriched in male individuals referred for diagnostic genetic testing of muscular dystrophy and has been observed in individual(s) with mild features of dystrophinopathy as well as in some unaffected individuals (PMID: 21104870; internal data). This missense change has been observed to be homozygous, hemizygous or homoplasmic in an individual who did not have the expected clinical features for that genetic result (internal data). ClinVar contains an entry for this variant (Variation ID: 161220). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DMD protein function with a negative predictive value of 95%. In summary, this variant is reported to cause disease. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the DMD gene, it has been classified as Pathogenic (low penetrance). -

Mar 12, 2019

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Neuromuscular disease caused by qualitative or quantitative defects of dystrophin Pathogenic:1

Oct 09, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DMD c.1724T>C (p.Leu575Pro) results in a non-conservative amino acid change located in the Central rod domain: Repeat 3 of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183132 control chromosomes. c.1724T>C has been reported in the literature in multiple individuals affected with Dystrophinopathies (example, (Becker_2021, Railean_2022, Tavallaee_2022, Herman_MN). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25637381, 35135626, 33146414, 33644936, 31648988, 36409343, 26365249, 21104870, Railean et al). ClinVar contains an entry for this variant (Variation ID: 161220). Based on the evidence outlined above, the variant was classified as pathogenic. -

Muscular dystrophy Pathogenic:1

Oct 08, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Becker muscular dystrophy (MIM#300376), Duchenne muscular dystrophy (MIM#310200) and dilated cardiomyopathy 3B (MIM#302045). (I) 0109 - This gene is associated with X-linked recessive disease. This gene is primarily associated with X-linked recessive disease relating to the muscular dystrophy phenotypes; however, it is also associated with X-linked DCM in heterozygous females (OMIM, GeneReviews, PMID: 26066469). (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 v3 (6 heterozygotes, 0 homozygotes, 3 hemizygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Spectrin repeats superfamily domain (NCBI, UniProt). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant is predominantly reported to be associated with mild symptoms of muscular dystrophy and increased creatine kinase (CK) and has been reported in individuals with BMD, DMD, and non-ischemic DCM (ClinVar, LOVD, PMID’s: 36409343, 35135626, 33644936, 21104870, 31648988). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Exertional myalgia, muscle stiffness and myoglobinuria Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Dilated cardiomyopathy 3B Uncertain:1

Mar 12, 2019

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Cardiovascular phenotype Uncertain:1

May 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L575P variant (also known as c.1724T>C), located in coding exon 15 of the DMD gene, results from a T to C substitution at nucleotide position 1724. The leucine at codon 575 is replaced by proline, an amino acid with similar properties. This variant has been detected in three pediatric-aged males with elevated serum CK and other signs of myopathy including exertional myalgia and abnormal muscle biopsies. However, dystrophin immunostaining and Western blot analyses were reportedly normal (Veerapandiyan A et al. Muscle Nerve, 2010 Dec;42:975-9). This variant (referred to as p.L567P, c.1700T>C) has been seen in an exome cohort, but clinical history was not provided (Amendola LM et al. Genome Res, 2015 Mar;25:305-15). Based on data from gnomAD, the C allele has an overall frequency of <0.01% (1/22008) total alleles studied, with 0 hemizygotes observed. The highest observed frequency was <0.01% (1/10867) of European (non-Finnish) alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	.;D;.;.;D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;.;D;D;D;T
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D
MetaSVM	Uncertain	0.26	D
PhyloP100		7.7
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.7	.;D;.;D;D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	.;D;.;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;.;.;D;.
Vest4		0.94
MVP		0.99
MPC		0.13
ClinPred		0.97	D
GERP RS		5.2
gMVP		0.86
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs370644567; hg19: chrX-32591735;